Retinal and choroidal efficacy of switching treatment to faricimab in recalcitrant neovascular age related macular degeneration

Aim of this study was to evaluate the efficacy of switching treatment to faricimab in neovascular age-related macular degeneration (nAMD) from other anti-VEGF agents. Fifty-eight eyes of fifty-one patients with nAMD and a full upload series of four faricimab injections were included. Demographic data, multimodal imaging and treatment parameters were recorded. The primary outcome measures were changes in central subfield thickness (CST) and subfoveal choroidal thickness (SFCT). A subgroup analysis was performed for eyes with prior ranibizumab (R) or aflibercept (A) treatment. Mean injection intervals before and after switching were comparable (33.8 ± 11.2 vs. 29.3 ± 2.6 days; p = 0.08). Mean CST of 361.4 ± 108.1 µm prior to switching decreased significantly to 318.3 ± 97.7 µm (p < 0.01) after the third faricimab injection, regardless of prior anti-VEGF treatment (p < 0.01). Although SFCT slightly improved for the whole cohort from 165.8 ± 76.8 µm to 161.0 ± 82,8 µm (p = 0.029), subgroup analysis did not confirm this positive effect (subgroup R: p = 0.604; subgroup A: p = 0.306). In patients with a suboptimal response to aflibercept or ranibizumab in nAMD, farcimab can improve CST and slightly improve or maintain SFCT. Further prospective randomized trials are warranted.


Multimodal imaging
Multimodal imaging was performed as needed and included SD-OCT and near infrared (NIR) scanning using the Spectralis HRA + OCT, Heidelberg Engineering system at each visit.At first diagnosis, fluorescein angiography was performed prior to treatment initiation.Automated CST measurements were obtained from the Heidelberg Eye Explorer (Version 1.10.12.0) after segmentation was manually corrected, if needed.Subfoveal choroidal thickness (SFCT) was measured directly under the fovea in the 1:1 µm display mode from the outer portion of the retinal pigment epithelium to the sclerochoroidal interface.If the chorioscleral border could not be visualized due to a thick choroid, the EDI mode (enhanced depth imaging) was additionally switched on.OCT data was collected from the the date of therapy initiation for nAMD (T1), the last three visits with intravitreal injections before switching to faricimab (T2-T4) and the first three faricimab intravitreal injections of loading phase (T5-T7).

Anti-VEGF treatment
Prior injection therapy included aflibercept (subgroup A) or ranibizumab (subgroup R).All patients received a faricimab loading of three injections every 30 days ± 7 days, after which the interval was extended based on the discretion of the doctor.Each injection contained 6 mg faricimab.MNV activity was defined as new macular fluid including IRF and SRF, PED or increasing CST.

Data analysis and statistics
Data management was done using Microsoft Excel Version 16.72 for Mac.Statistical analysis was performed in IBM SPSS® Statistics 28 (IBM Germany GmbH).Significance level was set at p < 0.05.Shapiro-Wilk test showed no normal distribution.Friedman test was used to analyze CST during the treatment period.Post hoc analysis was then applied for the pairwise comparison of the values.The Cohen´s effect size of the Friedman test was calculated using the formula r = (z/√n), where r < 0.3 corresponds to a weak effect, 0.3-0.5 to a medium effect, and > 0.5 to a strong effect.

Visual acuity measurements:
Visual acuity (VA) was documented in decimal VA and then converted to logarithm of the minimum angle resolution (LogMAR) units for analysis.Visual acuity was measuret throughout faricimab loading phase (T4-T7) or a small number of patients, the visual acuity values were missing at previous time points, particularly at initial diagnosis.The electronic chart had not yet been established for all patients at that time, so no visual acuity values were recorded electronically.

Baseline demographics
In total, 58 eyes of 51 patients were included in our analysis.Baseline demographics are summarized in Table 1.Average age at nAMD diagnosis was 75.2 ± 7.1 years, gender ratio was 25 male and 33 female.On average, patients received 37.5 ± 25.9 anti-VEGF injections prior to switching, consisting of 13.5 ± 14.7 ranibizumab and 24.0 ± 21.6 aflibercept injections on average.Average period from initial treatment to the point of switching to faricimab was 4.2 years.All faricimab injections were performed every 30 days ± 7 days.Mean injection intervals before and after switching were comparable (33.8 ± 11.2 vs. 29.3± 2.6 days; p = 0.08).There were no severe ocular complications recorded during this follow up period (no cases of intraocular inflammation, retinal detachment, severe spikes in IOP, intraocular hemorrhages or tears of the retinal pigment epithelium).

Fluid, CMT and SFCT dynamics
At baseline, all eyes showed MNV activity with IRF/SRF or PED.OCT at initial diagnosis showed PED in 57 eyes (98.3%),SRF was detected in all eyes and 20 eyes (34.5%) had additional IRF.CST measurements at each visit are shown in Table 2. Friedman Test showed a significant difference between measurements during T1-T7 (p < 0.01) (Table 3).Reduction of CST during the study period is shown in Figs. 1 and 2. CST improved from T1 to T4, however not significantly (p = 0.102).Between T2 and T4, CST remained similar (p = 0.184).Further improvement was noted from T4 to T7 (after three faricimab injections).Paired comparison showed a significant www.nature.com/scientificreports/difference between start (T4) and end (T7) of faricimab loading dose (p < 0.01, r = 0.4).After switching, an improvement in CST was noted in 91.4% (53 eyes).In five eyes (8.6%), an increase in CST compared to OCT measurement at the baseline visit was noted.19 eyes (32.8%) had remaining IRF, 4 eyes SRF ( 6.9%) and 2 eyes IRF and SEF (3.4).In total, 33 out of 58 eyes (56.0%) had a completely dry macula after the third faricimab injection.Remaining PED at the end of loading dose was detected in 26 eyes (44.8%).SFCT measurements at each visit are shown in Tables 4 and 5. SFCT also decreased significantly, although the effect power was low (p = 0.029, r = 0.2). Figure 3 shows examples of faricimab treatment effect in OCT.
In a subgroup analysis, CST and SFCT were examined during the treatment period in dependence on the prior drug ranibizumab or aflibercept just before the switch to faricimab.In total, 14 patients received      ranibizumab (subgroup R), 44 patients received aflibercept (subgroup A).CST decreased significantly in both groups (subgroup R: p = 0.014 r: 0.5; subgroup A: p < 0.01, r: 0.2).Although SFCT slightly improved for the whole cohort, subgroup analysis did not confirm this positive effect (subgroup R: p = 0.604; subgroup A: p = 0.306).

Visual acuity measurements
Visual acuity did not change significantly during loading phase with farcimab (p = 1,0).Mean visual acuity measurements are shown in Table 6 and pairwise comparison between time point is demonstrated in Table 7.

Discussion
The clinical introduction of faricimab as a novel treatment for nAMD is of particular interest in ophthalmology 13 .This study confirms that patients inadequately managed with ranibizumab and aflibercept for nAMD can benefit from switching treatment to faricimab to improve CST and maintain, or even slightly improve SFCT.
In this study, an inadequate response to anti-VEGF treatment was defined as persistent fluid in spite of 4-weekly dosing, or the inability to extend treat & extend intervals beyond 4 or 6 weeks.In real life studies with ranibizumab and aflibercept, continuous treatment intervals of 4 weeks were shown to be needed in 19-27% of eyes 14,15 , indicating a large population of patients possibly benefitting from treatment switches to newer, longerlasting anti-VEGF agents.
To this end, novel anti-VEGF molecules as well as bispecific approaches have been investigated.Faricimab as a bispecific antibody against VEGF-A and the Ang2/Tie-2 pathway raised promising expectations in preclinical evidence in terms of vascular stability and reducing leakage 16 which were confirmed in large phase III clinical trials 7,9 .
To our knowledge, only a few trials have been conducted to investigate the efficacy of faricimab in a real-world setting since its approval 13,[17][18][19][20][21][22][23][24] .These few published studies are mainly related to therapy-naïve patients, and there is little data on the outcome of faricimab therapy after pretreatment with other intravitreal drugs.Aim of the present study was to evaluate the short term response after switching to faricimab treatment following prior anti-VEGF treatment.
In the current study we focused on the morphological outcomes in OCT during loading phase of faricimab.OCT allows for a fast, accurate and quantitative assessment of nAMD and has established itself as an effective diagnostic standard in AMD 5,25 .CST is one of the main CNV activity markers, it provides a good readily comparable reference point 5 .Beside CST being an OCT progression marker, SFCT should also be of interest.Growth of choroidal vessels is affected by the retinal pigment epithelium mediated by VEGF 16,26,27 .There are controversial findings in literature, however VEGF inhibition can lead to a SFCT thinning by inducing Table 6.Visual acuity (VA) measurements during study period (T1-T7).www.nature.com/scientificreports/vasoconstriction and reduction of choriocapillaris endothelial cell fenestrations.Additionally SFCT thinning could also be secondary to suppression of the CNV activity 28 .Not only VEGF receptors are expressed in the choroid, furthermore Ang1/Tie2 receptors, maintain the choroidal vessels 29 .As faricimab affects both receptors, its impact could be greater than anti-VEGF inhibitors.Although all eyes in the present study had a long history of pretreatment, having received on average 38.4 ± 26.7 anti-VEGF injections before starting faricimab, the clinical response was only limited.In spite of the heavy pretreatment, faricimab nevertheless allowed for improvements in CST.Additionally, limited effects on SFCT were observed.SFCT, representing the perfusion origin of MNV, has been shown to influence anti-VEGF outcomes in nAMD eyes, especially those with a thick-choroid phenotype, e.g.PCV 30 .As this study presents the short-term effects after the loading phase, further studies assessing the possibility of treatment interval extension based on these.
Tenaya and Lucerne as phase 3 clinical studies compared faricimab to aflibercept in treatment naïve eyes.Faricimab provided equal functional and morphological outcomes with an interval of up to sixteen weeks 9 .This phase 3 studies were conducted with treatment naïve eyes, so a greater improvement in VA and CST in comparison with pre-treated eyes is expected 13 .Despite these results raising promising expectations, the effect of faricimab in clinical practice now needs to be verified in treatment naïve and pretreated patients.In this context, our data present real-world outcomes of treatment switch in pretreated eyes.Our findings correlate well with other studies on the subject.Stanga et al. evaluated VA and CST in 11 eyes early on after approval.Follow up time was only four weeks in this early published study.Both VA and CST improved 17 .Although those first and early results seemed to be promising, follow up time was short and cohort size small.Two Japanese studies of 2023 showed a decrease in central foveal and choroidal thickness, as well as an increase in VA within the first 3 month of faricimab loading in treatment naïve patients 18,29 .Overall, the morphological outcomes after faricimab were comparable to those after aflibercept treatment 23 .Even in treatment resistant AMD, faricimab can lead to an improved CST and VA even in treatment resistant AMD 13,31 .Kichi et al. found a decrease in CST without an improvement in VA, however treatment intervals could be prolongated 32 .Consistent with existing studies, we could verify these results in the documented CST decrease.
In line with recent studies investigating the effect of faricimab in pre-treated eyes, we did not find any significant improvement in visual acuity within the loading phase [19][20][21][22] .As shown in Table 6, the visual acuity values are highly variable.Visual acuity measured at a single measurement point in everyday clinical practice is highly dependent on the examiner, general condition and cohabitation.Therefore, the main criterion, especially in such a short period of time as the loading phase, are the image morphological changes.Interestingly, improvements were readily seen after the first faricimab injection.However, subsequent injections maintained this effect but did not significantly improve it.The effect power of 0.4 corresponds to a medium sized effect.Among patients receiving ranibizumab therapy immediately before the switch, the effect was greater compared to patients previously receiving aflibercept.On the other hand, not every eye showed a favorable response to faricimab.As shown in Fig. 2, eyes with a weak faricimab response do exist and reswitching to prior treatment should be considered.
There are certain limitations to this study, including its small sample size and short-follow up.Longer and larger trials, ideally designed as randomized cross-over trials, are warranted.Moreover, patients included in this study had undergone a relatively higher number of injections before switching to faricimab.Therefore, the extensive duration of prior treatment could mask an even better anatomical response in naïve or short-term treated eyes.Additionally, real world usability of new pharmaceutical agents does not only rely on efficacy, but also on safety.Our study was not powered to detect rare events like intraocular inflammation, however, our study does not add new adverse events to the published data.
In conclusion, our data support the efficacy of switching treatment in eyes with nAMD not adequately responding to older anti-VEGF agents.Future studies should observe not only the ability to extend treatment intervals, but also the long-term course both functionally and morphologically. https://doi.org/10.1038/s41598-024-59632-0

Table 1 .
Baseline demographics, including age, gender, CNV type and prior intravitreal injection therapy.

Table 3 .
Central subfield thickness in pairwise comparison.Bold: significant p-values.